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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

The EMBO journal | Jun 1, 2011

Tumour suppressor p53 levels in the cell are tightly regulated by controlled degradation through ubiquitin ligases including Mdm2, COP1, Pirh2, and ARF-BP1. The ubiquitination process is reversible via deubiquitinating enzymes, such as ubiquitin-specific peptidases (USPs). In this study, we identified ubiquitin-specific peptidase 4 (USP4) as an important regulator of p53. USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels. Usp4 knockout mice are viable and developmentally normal, but showed enhanced apoptosis in thymus and spleen in response to ionizing radiation. Compared with wild-type mouse embryonic fibroblasts (MEFs), Usp4-/- MEFs exhibited retarded growth, premature cellular senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints, consistent with upregulated levels and activity of p53 in the absence of USP4. Finally, we showed that USP4 is overexpressed in several types of human cancer, suggesting that USP4 is a potential oncogene.

Pubmed ID: 21522127 RIS Download

Mesh terms: Animals | Apoptosis | Cells, Cultured | Fibroblasts | Gene Knockout Techniques | Mice | Mice, Knockout | Oncogene Proteins | Proto-Oncogene Proteins | Radiation, Ionizing | Radiography | Spleen | Thymus Gland | Tumor Suppressor Protein p53 | Ubiquitin Thiolesterase | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA136549
  • Agency: NCRR NIH HHS, Id: 5P20RR017698
  • Agency: NCRR NIH HHS, Id: P20 RR017698
  • Agency: NINDS NIH HHS, Id: R01 NS072420
  • Agency: NCI NIH HHS, Id: R01CA136549

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